Engineering Multi-Tissue Interfaces

描述（由申请人提供）：关节是一个复杂的系统，经常受到创伤、炎症和代谢过程的影响。在美国，超过2000万人患有有症状的骨关节炎，并患有一些关节衰弱，因此开发干预性和再生性医疗是国家的优先事项。我们的项目旨在更好地了解骨/软骨界面的发展，以重建关节，如颞下颌关节（TMJ）。该提案的长期目标是制定多组织界面再生策略，重点是骨-软骨界面。我们提出了一个假设和设计驱动的组织工程项目，基于生物工程支架的快速制造，具有定制的表面化学，控制生物活性因子的空间和时间释放，以再生骨和软骨界面。该界面的受控生成将通过体内再生基因治疗方法来指导。中心假设是将生物活性信号传导因子（BMP-2和Sox 9）递送到设计的支架的不同区域可以控制响应细胞的谱系定型以形成骨/软骨界面。1.定制具有精确设计的生物信号特性的生物材料的表面化学。聚5-己内酯（PCL）表面将通过化学气相沉积（CVD）进行改性，以建立具有各种聚合物特性和共轭化学的表面涂层。三种不同的固定化模型将在这个特定的目标，以获得最大的控制病毒释放，通过生物素/抗生物素蛋白和生物材料的相互作用的动态平衡。2.将两种不同的病毒固定在一个支架上，以控制特定生物信号因子的传递，并了解这些信号如何控制生物界面的发育。材料表面将被修饰以控制多种腺病毒的递送。双向CVD也将用于产生信号梯度，以模拟界面处的自然发育信号模式。3.通过在设计的生物材料支架上使用体内再生基因转移策略引导响应细胞向骨和软骨的谱系进展来开发骨-软骨界面。将在体内生物材料支架上产生组织界面。将通过在支架的一个区域上递送BMP-2并在相邻表面上递送拮抗剂如头蛋白或显性负性BMP受体来研究界面发育的精度。骨/软骨界面的发育将通过BMP-2（骨）和Sox-9（软骨）的受控递送在体内进行研究。 公共卫生相关性：当先天性异常、创伤性损伤或炎性和退行性疾病涉及关节连接关节如颞下颌关节（TMJ）时，其影响通常是身体、经济和情感上的衰弱。不幸的是，尽管有几十年的有针对性的临床和基础科学研究，修复或再生这种关节的成熟方法仍然难以实现，导致临床需求严重不足。这项提案的长期目标是制定策略，再生骨软骨界面，以再生关节，如颞下颌关节。

DESCRIPTION (provided by applicant): The articulating joint is a complex system that is regularly subjected to trauma, inflammatory and metabolic processes. More than 20 million individuals in the United States have symptomatic osteoarthritis and suffer from some debilitation of the joints and therefore developing interventive and regenerative medical cures is a national priority. Our projects are aimed at gaining a greater understanding of the development of bone/cartilage interfaces for the reconstruction of articular joints such as the temporomandibular joint (TMJ). The long-term objective of this proposal is to develop strategies to regenerate multi-tissue interfaces with a focus on the bone-cartilage interface. We propose a hypothesis and design-driven tissue engineering project based on rapid fabrication of bioengineered scaffolds, with custom-tailored surface chemistry, that control the spatial and temporal release of bioactive factors to regenerate the bone and cartilage interface. The controlled generation of this interface will be directed via an in vivo regenerative gene therapy approach. The central hypothesis is that delivery of bioactive signaling factors (BMP-2 and Sox9) to distinct regions of designed scaffolds can control the lineage commitment of responsive cells to develop a bone/cartilage interface. 1. To custom-tailor the surface chemistry of biomaterials with precisely designed biological signaling properties. Poly 5-caprolactone (PCL) surfaces will be modified by chemical vapor deposition (CVD) to establish surface coatings with a variety of polymer properties and conjugation chemistries. Three different immobilization models will be developed in this specific aim to gain maximal control of viral release through a dynamic equilibrium of biotin/avidin and biomaterial interactions. 2. To immobilize two different viruses on a single scaffold to control delivery of specific biological signaling factors and to understand how these signals control the development of a biological interface. Material surfaces will be modified to control the delivery of multiple adenoviruses. Two-way CVD will also be used to generate signaling gradients to mimic natural developmental signaling patterns at an interface. 3. To develop a bone-cartilage interface by directing the lineage progression of responsive cells to bone and cartilage using in vivo regenerative gene transfer strategies on designed biomaterial scaffolds. Tissue interfaces will be generated on biomaterial scaffolds in vivo. The precision of interface development will be studied by delivering BMP-2 on one region of a scaffold and antagonists such as noggin or dominant negative BMP receptors on the adjacent surfaces. The development of bone/cartilage interfaces will be studied in vivo by the controlled delivery of BMP-2 (bone) and Sox-9 (cartilage). PUBLIC HEALTH RELEVANCE: When congenital anomalies, traumatic injuries or inflammatory and degenerative diseases involve an articulating joint such as the temporomandibular joint (TMJ), the effects are often physically, financially and emotionally debilitating. Unfortunately, despite decades of targeted clinical and basic science research, well established methods to repair or regenerate such joints remain elusive, resulting in a significant unmet clinical need. The long-term objective of this proposal is to develop strategies to regenerate the bone-cartilage interface to regenerate joins like the TMJ.